drGT: Attention-Guided Gene Assessment of Drug Response Utilizing a Drug-Cell-Gene Heterogeneous Network

TL;DR

drGT is a novel heterogeneous graph deep learning model that predicts drug response with high accuracy and provides mechanism-oriented interpretability through attention coefficients, integrating biological plausibility and literature support.

Contribution

It introduces drGT, a new graph-based model that combines drug, gene, and cell line data for improved prediction and interpretability of drug response.

Findings

Achieves top regression performance with AUROC up to 0.945

Maintains competitive classification accuracy for drug sensitivity

Provides biologically plausible drug-gene links supported by literature

Abstract

For translational impact, both accurate drug response prediction and biological plausibility of predictive features are needed. We present drGT, a heterogeneous graph deep learning model over drugs, genes, and cell lines that couples prediction with mechanism-oriented interpretability via attention coefficients (ACs). We assess both predictive generalization (random, unseen-drug, unseen-cell, and zero-shot splits) and biological plausibility (use of text-mined PubMed gene-drug co-mentions and comparison to a structure-based DTI predictor) on GDSC, NCI60, and CTRP datasets. Across benchmarks, drGT consistently delivers top regression performance while maintaining competitive classification accuracy for drug sensitivity. Under random 5-fold cross-validation, drGT attains an AUROC of up to 0.945 (3rd overall) and an $R^2$ up to 0.690, outperforming all baselines on regression. In leave-one-out tests for unseen cell lines and drugs, drGT achieves AUROCs of 0.706 and 0.844, and $R^2$ values of 0.692 and 0.022, the only model yielding positive $R^2$ for unseen drugs. In zero-shot prediction, drGT achieves an AUROC of 0.786 and a regression $R^2$ of 0.334, both representing the highest scores among all models. For interpretability, AC-derived drug-gene links recover known biology: among 976 drugs with known DTIs, 36.9% of predicted links match established DTIs, and 63.7% are supported by either PubMed abstracts or a structure-based predictive model. Enrichment analyses of AC-prioritized genes reveal drug-perturbed biological processes, providing pathway-level explanations. drGT advances predictive generalization and mechanism-centered interpretability, offering state-of-the-art regression accuracy and literature-supported biological hypotheses that demonstrate the use of graph learning from heterogeneous input data for biological discovery. Code: https://github.com/sciluna/drGT